Haplotypes and gene expression implicate the MAPT region for Parkinson disease -: The GenePD Study
Haplotypes and gene expression implicate the MAPT region for Parkinson disease -: The GenePD Study
复制标题
DOI：
10.1212/01.wnl.0000304051.01650.23
复制
发表时间：
2008-07-01
期刊：
影响因子：
9.9
通讯作者：
Myers, R. H.
中科院分区：
文献类型：
--
作者：
Tobin, J. E.;Latourelle, J. C.;Myers, R. H.
背景：微管相关蛋白tau(MAPT)与多种神经退行性疾病有关，包括帕金森病和帕金森病。在GenePD研究招募的大量家族性PD病例中，我们评估了MAPT区域与PD的相关性。此外，采用帕金森病患者和神经学正常对照的死后脑组织标本，研究MAPT的3-重复和4-重复亚型及其邻近基因Saitohin(STH)和KIAA1267在PD小脑中的表达是否发生改变。方法：对位于染色体17q21的MAPT区域的21个单核苷酸多态(SNPs)进行基因分型。单个SNP和单倍型，包括H1单倍型，被评估与帕金森病的关联。结果：调整多重比较后，SNP rs1800547与帕金森病显著相关。虽然H1单倍型与帕金森病风险显著增加相关，但发现了一种新的H1亚单倍型，预测帕金森病风险增加更大。4-重复MAPT、STH和KIAA1267在帕金森病患者脑组织中的表达显著高于对照组。结论：本研究支持MAPT在家族性和特发性帕金森病(PD)发病机制中的作用。有趣的是，基因表达研究的结果表明，MAPT附近的其他基因，特别是STH和KIAA1267，可能也在帕金森病中起作用，并提示该区域的基因对帕金森病风险有复杂的影响。
Background: Microtubule-associated protein tau ( MAPT) has been associated with several neurode-generative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum.Methods: Twenty-one single-nucleotide polymorphisms ( SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR.Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT.Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease ( PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.